Nigral GFRα1 infusion in aged rats increases locomotor activity, nigral tyrosine hydroxylase, and dopamine content in synchronicity

Brandon S. Pruett, Michael Francis Salvatore

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

Delivery of exogenous glial cell line-derived neu-rotrophic factor (GDNF) increases locomotor activity in rodent models of aging and Parkinson's disease in conjunction with increased dopamine (DA) tissue content in sub-stantia nigra (SN). Striatal GDNF infusion also increases expression of GDNF's cognate receptor, GFRα1, and tyro-sine hydroxylase (TH) ser31 phosphorylation in the SN of aged rats long after elevated GDNF is no longer detectable. In aging, expression of soluble GFRα1 in the SN decreases in association with decreased TH expression, TH ser31 phosphorylation, DA tissue content, and locomotor activity. Thus, we hypothesized that, in aged rats, replenishing soluble GFRα1 in SN could reverse these deficits and increase locomotor activity. We determined that the quantity of soluble GFRα1 in young adult rat SN is ∼3.6 ng. To replenish age-related loss, which is ∼30 %, we infused 1 ng soluble GFRα1 bilaterally into SN of aged male rats and observed increased locomotor activity compared to vehicle-infused rats up to 4 days following infusion, with maximal effects on day 3. Five days after infusion, however, neither locomotor activity nor nigrostriatal neurochemical measures were significantly different between groups. In a separate cohort of male rats, nigral, but not striatal, DA, TH, and TH ser31 phosphorylation were increased 3 days following unilateral infusion of 1 ng soluble GFRα1 into SN. Therefore, in aged male rats, the transient increase in locomotor activity induced by replenishing age-related loss of soluble GFRα1 is temporally matched with increased nigral dopaminergic function. Thus, expression of soluble GFRα1 in SN may be a key component in locomotor activity regulation through its influence over TH regulation and DA biosynthesis.

Original languageEnglish
Pages (from-to)988-999
Number of pages12
JournalMolecular Neurobiology
Volume47
Issue number3
DOIs
StatePublished - 1 Jan 2013

Fingerprint

Tyrosine 3-Monooxygenase
Substantia Nigra
Locomotion
Mixed Function Oxygenases
Dopamine
Neuroglia
Corpus Striatum
Phosphorylation
Cell Line
Glial Cell Line-Derived Neurotrophic Factor Receptors
Parkinson Disease
Young Adult
Rodentia

Keywords

  • Aging
  • Bradykinesia
  • Dopamine
  • GFRα1
  • Parkinsonism
  • Striatum
  • Substantia nigra
  • Tyrosine hydroxylase

Cite this

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title = "Nigral GFRα1 infusion in aged rats increases locomotor activity, nigral tyrosine hydroxylase, and dopamine content in synchronicity",
abstract = "Delivery of exogenous glial cell line-derived neu-rotrophic factor (GDNF) increases locomotor activity in rodent models of aging and Parkinson's disease in conjunction with increased dopamine (DA) tissue content in sub-stantia nigra (SN). Striatal GDNF infusion also increases expression of GDNF's cognate receptor, GFRα1, and tyro-sine hydroxylase (TH) ser31 phosphorylation in the SN of aged rats long after elevated GDNF is no longer detectable. In aging, expression of soluble GFRα1 in the SN decreases in association with decreased TH expression, TH ser31 phosphorylation, DA tissue content, and locomotor activity. Thus, we hypothesized that, in aged rats, replenishing soluble GFRα1 in SN could reverse these deficits and increase locomotor activity. We determined that the quantity of soluble GFRα1 in young adult rat SN is ∼3.6 ng. To replenish age-related loss, which is ∼30 {\%}, we infused 1 ng soluble GFRα1 bilaterally into SN of aged male rats and observed increased locomotor activity compared to vehicle-infused rats up to 4 days following infusion, with maximal effects on day 3. Five days after infusion, however, neither locomotor activity nor nigrostriatal neurochemical measures were significantly different between groups. In a separate cohort of male rats, nigral, but not striatal, DA, TH, and TH ser31 phosphorylation were increased 3 days following unilateral infusion of 1 ng soluble GFRα1 into SN. Therefore, in aged male rats, the transient increase in locomotor activity induced by replenishing age-related loss of soluble GFRα1 is temporally matched with increased nigral dopaminergic function. Thus, expression of soluble GFRα1 in SN may be a key component in locomotor activity regulation through its influence over TH regulation and DA biosynthesis.",
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Nigral GFRα1 infusion in aged rats increases locomotor activity, nigral tyrosine hydroxylase, and dopamine content in synchronicity. / Pruett, Brandon S.; Salvatore, Michael Francis.

In: Molecular Neurobiology, Vol. 47, No. 3, 01.01.2013, p. 988-999.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Nigral GFRα1 infusion in aged rats increases locomotor activity, nigral tyrosine hydroxylase, and dopamine content in synchronicity

AU - Pruett, Brandon S.

AU - Salvatore, Michael Francis

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N2 - Delivery of exogenous glial cell line-derived neu-rotrophic factor (GDNF) increases locomotor activity in rodent models of aging and Parkinson's disease in conjunction with increased dopamine (DA) tissue content in sub-stantia nigra (SN). Striatal GDNF infusion also increases expression of GDNF's cognate receptor, GFRα1, and tyro-sine hydroxylase (TH) ser31 phosphorylation in the SN of aged rats long after elevated GDNF is no longer detectable. In aging, expression of soluble GFRα1 in the SN decreases in association with decreased TH expression, TH ser31 phosphorylation, DA tissue content, and locomotor activity. Thus, we hypothesized that, in aged rats, replenishing soluble GFRα1 in SN could reverse these deficits and increase locomotor activity. We determined that the quantity of soluble GFRα1 in young adult rat SN is ∼3.6 ng. To replenish age-related loss, which is ∼30 %, we infused 1 ng soluble GFRα1 bilaterally into SN of aged male rats and observed increased locomotor activity compared to vehicle-infused rats up to 4 days following infusion, with maximal effects on day 3. Five days after infusion, however, neither locomotor activity nor nigrostriatal neurochemical measures were significantly different between groups. In a separate cohort of male rats, nigral, but not striatal, DA, TH, and TH ser31 phosphorylation were increased 3 days following unilateral infusion of 1 ng soluble GFRα1 into SN. Therefore, in aged male rats, the transient increase in locomotor activity induced by replenishing age-related loss of soluble GFRα1 is temporally matched with increased nigral dopaminergic function. Thus, expression of soluble GFRα1 in SN may be a key component in locomotor activity regulation through its influence over TH regulation and DA biosynthesis.

AB - Delivery of exogenous glial cell line-derived neu-rotrophic factor (GDNF) increases locomotor activity in rodent models of aging and Parkinson's disease in conjunction with increased dopamine (DA) tissue content in sub-stantia nigra (SN). Striatal GDNF infusion also increases expression of GDNF's cognate receptor, GFRα1, and tyro-sine hydroxylase (TH) ser31 phosphorylation in the SN of aged rats long after elevated GDNF is no longer detectable. In aging, expression of soluble GFRα1 in the SN decreases in association with decreased TH expression, TH ser31 phosphorylation, DA tissue content, and locomotor activity. Thus, we hypothesized that, in aged rats, replenishing soluble GFRα1 in SN could reverse these deficits and increase locomotor activity. We determined that the quantity of soluble GFRα1 in young adult rat SN is ∼3.6 ng. To replenish age-related loss, which is ∼30 %, we infused 1 ng soluble GFRα1 bilaterally into SN of aged male rats and observed increased locomotor activity compared to vehicle-infused rats up to 4 days following infusion, with maximal effects on day 3. Five days after infusion, however, neither locomotor activity nor nigrostriatal neurochemical measures were significantly different between groups. In a separate cohort of male rats, nigral, but not striatal, DA, TH, and TH ser31 phosphorylation were increased 3 days following unilateral infusion of 1 ng soluble GFRα1 into SN. Therefore, in aged male rats, the transient increase in locomotor activity induced by replenishing age-related loss of soluble GFRα1 is temporally matched with increased nigral dopaminergic function. Thus, expression of soluble GFRα1 in SN may be a key component in locomotor activity regulation through its influence over TH regulation and DA biosynthesis.

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KW - Dopamine

KW - GFRα1

KW - Parkinsonism

KW - Striatum

KW - Substantia nigra

KW - Tyrosine hydroxylase

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